Process for preparation of cefdinir

ABSTRACT

The present invention relates to a novel crystalline cefdinir intermediate having formula (II) which can be used very usefully for preparing a cephalosporin antibiotics, cefdinir, in which Ph represents phenyl, p-TsOH represents p-toluenesulfonic acid, and DMAC represents N,N-dimethylacetamide, to a process for preparation thereof and to a process for preparing cefdinir using the compound of formula (II). ##STR1## According to the present invention, cefdinir can be prepared in an excellent color and purity and with a good yield.

This application is the national phase of [claims priority under 35U.S.C. § 371 to] PCT Application No. PCT/KR96/00250 [100250], filed Dec.26, 1996.

TECHNICAL FIELD

The present invention relates to a process for preparing cefdinirrepresented by the following formula (I) as a cephalosporin antibiotics:##STR2##

BACKGROUND ART

Cefdinir of formula (I) above has a chemical name of7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cep-hem-4-carboxylicacid. It is the third generation of cephalosporin antibiotics for oraladministration and has a broader antibacterial spectrum over the generalgram positive and gram negative bacteria than other antibiotics for oraladministration. Particularly, it has been reported that cefdinir has anexcellent antibacterial activity against Staphylococci and Streptococci.

In U.S. Pat. No. 4,559,334 is disclosed a process for preparing cefdiniras represented in the following reaction scheme 1. ##STR3##

In the above reaction, 7-amino-3-vinyl-3-cephem-4-carboxylic acidester(A) is reacted with a reactive carboxylic acid derivative to obtainan 7-amido compound(B), and this compound is treated with a nitrosatingagent to prepare an N-oxime compound(C). Continually, the compound(C) iscyclized with thiourea to prepare an aminothiazol compound(D), and thenfinally cefdinir of formula (I) is prepared by removing the carboxyprotecting group.

In case cefdinir is prepared according to the reaction scheme 1,however, there can occur many problems such that the process forpreparing the 7-amido compound(B) should be carried out at a temperaturebelow -20° C. under an anhydrous condition and that the isolation of theN-oxime compound(C) may cause a lot of troubles in the procedure ofindustrialization since the compound(C) is obtained as a solid having asyrup or a foam phase after the solvent is distilled off under reducedpressure. In addition, the aminothiazole compound(D) is obtained in apoor yield and purity and with a brownish poor color, which finallyexerts a harmful influence upon the purity and color of the desiredcefdinir. Further, in the reaction scheme 1, since cefdinir issynthesized through a complicated reaction consisting of 4 steps fromthe expensive 7-amino-3-vinyl-3-cephem-4-carboxylic acid derivative, thecost for production of cefdinir increases according as the wholereaction yield decreases.

DISCLOSURE OF INVENTION

Thus, the present inventors have extensively studied to develop a novelprocess by which cefdinir can conveniently be prepared in a good yieldand a high purity. As a result, we have identified that such a purposecan be achieved by using a novel cefdinir intermediate represented bythe following formula (II) as a starting substance and then completedthe present invention. ##STR4## in which Ph represents phenyl,

p-TsOH represents p-toluenesulfonic acid, and

DMAC represents N,N-dimethylacetamide.

Thus, it is an object of the present invention to provide a novelprocess for preparing cefdinir using the intermediate of formula (II) asa starting substance.

It is another object of the present invention to provide a novelintermediate of formula (II), as defined above, and process forpreparation thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In one aspect, the present invention pertains to a process for preparingcefdinir of formula (I) characterized in that a trityl protecting groupin the cefdinir intermediate of formula (II) is removed in the presenceof an acid. The process is depicted in the following reaction scheme 2.##STR5##

The most important feature in the process for preparing cefdiniraccording to the present invention is that the novel cefdinirintermediate of formula (II) which is very excellent in yield and purityis used as a starting material.

As the acid which can be used in the process for preparing cefdiniraccording to the present invention, an inorganic acid such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,Lewis acid, etc.; an organic acid such as acetic acid, formic acid,trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc.; or an acidic hydrogen ion exchange resincan be mentioned, wherein Lewis acid includes boron trifluoride, borontrifluoride ethyletherate, aluminum chloride, antimony pentachloride,ferrous chloride, stannous chloride, titanium tetrachloride, zincchloride, etc. When an organic acid such as trifluoroacetic acid orp-toluenesulfonic acid, or a Lewis acid is selected, it is preferablethat the reaction is carried out in the presence of an anisole as acation scavenger. The acid is preferably used in an amount of 1 to 20equivalents with respect to the starting material

It is preferable to carry out the reaction at a low temperature in arange of -30 to 5° C. But, the reaction can also be performed at 40 to70° C. in case of using the acid in an amount of 1 to 2 equivalents withrespect to the cefdinir intermediate of formula (II).

As the solvent, one or more selected from a group consisting of water,ethanol, methanol, propanol, t-butanol, tetrahydrofuran, dioxane,N,N-dimethylformamide, N,N-dimethylacetamide, methylene chloride andchloroform can be used, and if desired, the organic acid or inorganicacid itself can be used as a reaction solvent.

The cefdinir of formula (I) prepared according to the process asexplained above exhibits a superior quality in color, yield and purityto that prepared according to the earlier process, and such a result isbasically caused by use of the cefdinir intermediate of formula (II) asa starting material. That is, this intermediate is a crystallinecompound having a pale yellow color and a high purity more than 98%,therefore it's good quality has a beneficial effect on the next step forfinally producing cefdinir having an excellent quality.

Generally, the earlier process for preparing cefdinir from the reactivederivative has problems that 1-hydroxybenzotriazole or2-mercaptobenzothiazole produced during the reaction can hardly beremoved from the reaction mixture, which lowers the purity of thereaction product and also makes the purifying step difficult. Uponconsidering this, the present invention having no such problems can beestimated as an astounding one.

Furthermore, in the prior art, cefdinir can be prepared from theexpensive compound(A) through a 4-step reaction. In contrast, in thepresent invention, only 2 steps of reaction are needed for thepreparation of the final product, cefdinir. Therefore, a lot ofbeneficial effects can be expected by applying the present invention forpreparing cefdinir such that a decrease of the yield due to themulti-step reaction can be prevented; the product can be provided with alow price since there is no need to use the expensive material; and themanufacturing time, can be saved by cutting the reaction steps in half,and the like.

In another aspect, the present invention pertains to the compound offormula (II) above and process for preparing the same.

The cefdinir intermediate of formula (II) used as a starting material inthe reaction scheme 2 is a crystalline complex with a salt and asolvent, and it can easily be prepared by reacting a reactive esterhaving the following formula (III) with a 3-cephem derivative having thefollowing formula (IV) in a solvent in the presence or absence of a baseand then by adding p-toluenesulfonic acid thereto. The reaction isdepicted in the following reaction scheme 3: ##STR6## in which ##STR7##Z represents ##STR8## wherein R' represents C₁ -C₄ alkyl or phenyl, orR' together with phosphorus and oxygen atoms to which R' is attached canform a 5 to 6-membered heterocycle.

The reactive ester compound of formula (III) used as a startingsubstance in the reaction scheme 3 above is a known compound and can beprepared according to the process disclosed in literatures (see,European Patent Laid-open Publication No. 555,769; Japanese PatentLaid-open Publication No. sho 57-175,196). The 3-cephem derivative offormula (IV) can also be prepared easily according to the known methoddescribed in U.S. Pat. No. 4,423,213.

The reactive ester compound of formula (III) is used in an amount of 0.8to 2.0 equivalents, preferably 1.0 to 1.2 equivalents with respect tothe 3-cephem derivative of formula (IV). The solvent which can be usedin the reaction of scheme 3 includes, N,N-dimethylacetamide alone, or amixture of N,N-dimethylacetamide with one or more selected from a groupconsisting of ethanol, methanol, isopropanol, diethylether,tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile,ethyl acetate and acetone. In this case, the solvent is used in anamount of 10 to 60 ml, preferably 10 to 30 ml with respect to 1 g of the3-cephem derivative of formula (IV).

Generally, the reaction is carried out at a temperature of -15 to 40°C., preferably 0 to 30° C. The reaction is completed after 1 to 24 hourshave passed from the initial point, however, it is desirable to completethe reaction within 1 to 5 hours since the color of the reactionsolution becomes poor and the amount of side products increases as thereaction time becomes longer.

The process for preparing the compound (II) of the present invention canbe carried out in the presence of a base. If a base is used, tertiaryamines such as triethylamine, tri-n-butylamine, diisopropylethylamine,triethylenediamine, pyridine, N,N-dimethylaniline, etc., preferablytriethylamine or tri-n-butylamine can be used as the base. The base canbe used in an amount of 0.5 to 5 equivalents, preferably 1 to 2equivalents with respect to the 3-cephem derivative of formula (IV). Onthe other hand, the reaction can also be carried out by usingN-trimethylsilylacetamide or N,O-bistrimethylsilylacetamide in an amountof 1 to 3 equivalents with respect to the 3-cephem derivative of formula(IV) instead of the base.

After the reaction is completed under the conditions as explained above,diethylether, diisopropylether or ethylacetate is added to the reactionmixture to crystallize the product in the work-up procedure. In thiscase, they are added in an amount of 2 to 6 times by volume with respectto the reaction solvent, however, it is desirable to add them in anamount of 3 to 5 times by volume considering the reaction yield andpurity.

On the other hand, p-toluenesulfonic acid is usually used in an amountof 1 to 4 equivalents, preferably 2 to 3 equivalents with respect to the3-cephem derivative of formula (IV).

The cefdinir intermediate of formula (II) thus produced is a crystallinecomplex with a salt and a solvent, and it has a unique structure whereinone molecule of p-toluenesulfonic acid and two molecules ofN,N-dimethylacetamide are attached to the main structure. Accordingly,it can be isolated more easily from the reaction mixture in a highpurity than the usual cephalosporin compound having a noncrystallineform.

It is recognized through a X-ray powder diffraction analysis that thecompound (II) has a different crystalline form from other noncrystallinecompounds. Particularly, in the X-ray powder diffraction spectrum ofFIG. 1, the characteristic peak; of the compound (II) is wellrepresented. The unique Debye-Scherrer X-ray powder diffraction patternof the crystalline compound of formula (II) is described in thefollowing Table 1.

In Table 1 below, "θ" represents a diffraction angle, "d" represents aspacing between the layers, and "I/I_(o) " represents a relativeintensity.

                  TABLE 1                                                         ______________________________________                                        Debye-Scherrer X-ray powder diffraction pattern of the                          compound of formula (II)                                                        θ                                                                              d          I / Io                                                                             θ  d    I / Io                               ______________________________________                                        4.28   20.63      18     19.64    4.52 19                                       8.06 10.96 29 20.32 4.37 20                                                   8.36 10.57 38 20.62 4.31 51                                                   8.88 9.95 22 20.82 4.26 28                                                    9.14 9.67 18 21.06 4.21 46                                                    10.08 8.77 15 21.58 4.11 34                                                   11.22 7.88 34 21.76 4.08 23                                                   11.44 7.73 28 22.24 3.99 20                                                   12.02 7.36 33 22.58 3.93 18                                                   12.92 6.85 20 23.02 3.86 25                                                   13.28 6.66 32 23.34 3.81 17                                                   15.24 5.81 18 23.48 3.79 21                                                   15.56 5.69 27 24.24 3.67 39                                                   16.20 5.47 22 25.04 3.55 21                                                   16.76 5.29 19 25.12 3.54 16                                                   17.14 5.17 95 25.70 3.46 29                                                   17.24 5.14 81 26.04 3.42 19                                                   17.62 5.03 29 26.62 3.35 16                                                   18.14 4.89 69 27.22 3.27 17                                                   18.50 4.79 87 27.76 3.21 16                                                   18.54 4.78 100 29.28 3.05 18                                                  18.76 4.73 60 29.48 3.03 20                                                 ______________________________________                                    

In addition, the structure of the intermediate (II) is identifiedqualitatively through IR and NMR spectroscopy (see, FIG. 1 to 3)

Hereinafter, the present invention will be more specifically explainedby the following examples. However, it should be understood that thefollowing examples are intended to illustrate the present invention andnot to limit the scope of the present invention in any manner.

EXAMPLE 1

Synthesis of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluene sulfonic acid•2 N,N-dimethylacetamide

8.0 g (35.4 mmol) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid and 21.5g (37.1 mmol) of (Z)-(2-aminothiazol-4-yl)-2-trityloxyiminoacetic acid2-benzothiazolyl thioester were suspended in 80 ml ofN,N-dimethylacetamide and 16.8 ml (70.0 mmol) of tri-n-butylamine wasadded thereto. Then, the reaction mixture was stirred for 1 hour whilekeeping the temperature at 15 to 20° C. and 240 ml of diethylether wasadded to the mixture. The reaction mixture thus prepared was stirred for30 minutes and then filtered through a cellite. To the filtrate wasadded 20.2 g (0.11 mol) of p-toluenesulfonic acid•monohydrate dissolvedin 40 ml of methanol and the resulting solution was stirred for 2 hoursat room temperature. After 160 ml of diethylether was further addedthereto, the whole solution was stirred for one hour at roomtemperature, cooled to 0 to 5° C., stirred for one hour and filtered.The crystal thus obtained was washed sequentially with 50 ml ofN,N-dimethylacetamide-diethylether(1:5, v/v) and 50 ml of diethyletherand then dried to obtain 32.3 g (Yield 93%) of the title compound as apale yellow crystal.

HPLC Purity: 99.2%;

m.p.(°C.): 164-165;

IR(KBr, cm⁻¹): 3061, 1780, 1622, 1192;

¹ H-NMR(MeOH-d₄)δ: 2.0(s,6H), 2.3(s,3H), 2.9(s,6H), 3.0(s,6H),3.7(s,2H), 5.0-6.0(m,4H), 6.9-7.5(m,17H), 7.7(d,2H,J=8 Hz).

EXAMPLE 2

10.0 g (44.0 mmol) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid and27.0 g (46.4 mmol) of (Z)-(2-aminothiazol-4-yl)-2-trityloxyiminoaceticacid 2-benzothiazolylthioester were mixed in 200 ml ofN,N-dimethylacetamide. 22.0 ml (89.0 mmol) ofN,O-bistrimethylsilylacetamide was added thereto and then the resultingmixture was stirred overnight at 10 to 20° C. After 600 ml ofdiethylether and 10 ml of methanol were added to the mixture, the wholemixture was stirred for 30 minutes and then filtered through a cellite.To the filtrate was added 12.6 g (66.2 mmol) of p-toluenesulfonicacid•monohydrate dissolved in 40 ml of methanol and the resultingsolution was stirred for 3 hours. After 400 ml of diethylether wasfurther added thereto, the solution was stirred for 2 hours and thenfiltered. The crystal thus obtained was washed sequentially with 60 mlof N,N-dimethylacetamide-diethylether(1:5, v/v) and 100 ml ofdiethylether and then dried to obtain 38.3 g (Yield 88%) of7β-[2-(2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluenesulfonic acid•2 N,N-dimethylacetamide as a pale yellowcrystal. The purity of the product determined by HPLC analysis was99.4%, and melting point, IR and ¹ H-NMR data were identical to thosedescribed in Example 1.

EXAMPLE 3

18.9 g (32.5 mmol) of diethylthiophosphoryl(Z)-(2-aminothiazol-4-yl)-2-trityloxyiminoacetate was dissolved in 105ml of N,N-dimethyl acetamide. 7.0 g (31 mmol) of7-amino-3-vinyl-3-cephem-4-carboxylic acid and 8.6 ml (62 mmol) oftriethylamine were added thereto and then the resulting mixture wasstirred for 2 hours at room temperature. 210 ml of diethylether wasadded to the mixture, which was then stirred for 30 minutes and filteredthrough a cellite. To the filtrate was added 17.7 g (93 mmol) ofp-toluenesulfonic acid•monohydrate dissolved in 25 ml of ethanol and theresulting solution was stirred for one hour and a half. After 210 ml ofdiethylether was further added thereto, the solution was filtered toobtain a crystal. The crystal thus obtained was washed sequentially with50 ml of N,N-dimethylacetamide-diethylether(1:5, v/v) and 50 ml ofdiethylether and then dried to obtain 26.2 g (Yield 86%) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluenesulfonic acid•2 N,N-dimethylacetamide as a pale yellowcrystal. The purity of the product determined by HPLC analysis was98.5%, and melting point, IR and ¹ H-NMR data were identical to thosedescribed in Example 1.

EXAMPLE 4

10.0 g (44.0 mmol) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid and27.0 g (46.4 mmol) of (Z)-(2-aminothiazol-4-yl)-2-trityloxyiminoaceticacid 2-benzothiazolylthioester were suspended in 150 ml ofN,N-dimethylacetamide. 21.0 ml (88.0 mmol) of tri-n-butylamine was addedthereto and the mixture was stirred for 1 hour and a half at 15 to 25°C. 25.2 g (133 mmol) of p-toluenesulfonic acid•monohydrate was added tothe mixture and thoroughly dissolved, 450 ml of diisopropylether wasadded thereto and then the whole mixture was stirred for 2 hours. After300 ml of diisopropylether was added to the mixture, the resultingsolution was stirred for 2 hours, cooled to about 5° C., stirred for 1hour and filtered to obtain a crystal. The crystal thus obtained waswashed sequentially with 50 ml ofN,N-dimethylacetamide-diethylether(1:5, v/v) and 50 ml of diethyletherand then dried to obtain 41.8 g (Yield 96%) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluenesulfonic acid•2 N,N-dimethylacetamide as a pale yellowcrystal. The purity of the product determined by HPLC analysis was98.2%, and melting point, IR and ¹ H-NMR data were identical to thosedescribed in Example 1.

EXAMPLE 5

10.0 g (44.0 mmol) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid and30.8 g (53 mmol) of (Z)-(2-aminothiazol-4-yl)-2-trityloxyiminoaceticacid 2-benzothiazolylthioester were mixed in 200 ml ofN,N-dimethylacetamide. 21.1 ml (88 mmol) of tri-n-butylamine was addedthereto and then the resulting mixture was stirred overnight at roomtemperature. After 400 ml of diethylether and 2 g of activated charcoalwere added to the mixture, the whole mixture was stirred for 1 hour andthen filtered through a cellite. To the filtrate was added 16.8 g (88mmol) of p-toluenesulfonic acid•monohydrate dissolved in 30 ml ofmethanol and the resulting solution was stirred for 2 hours. After 400ml of diethylether was further added thereto, the solution was stirredfor 2 hours and then filtered. The crystal thus obtained was washedsequentially with 50 ml of N,N-dimethylacetamide-diethylether(1:5, v/v)and 50 ml of diethylether and then dried to obtain 37.0 g (Yield 85%) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluenesulfonic acid•2 N,N-dimethylacet-amide as a pale yellowcrystal. The purity of the product determined by HPLC analysis was98.5%, and melting point, IR and ¹ H-NMR data were identical to thosedescribed in Example 1.

EXAMPLE 6

Synthesis of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid

15.0 g (15.2 mmol) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluenesulfonic acid•2 N,N-dimethylacetamide was dissolved in 9ml of methanol and then 0.51 ml (15.2 mmol) of 99% formic acid was addedthereto. After the resulting mixture was stirred for 5 hours underreflux, the methanol contained therein was removed under reducedpressure and 50 ml of water, 30 ml of tetrahydrofuran and 60 ml ofethylacetate were added to the residue. The pH of the solution wasadjusted to 6.5 to 7.5 by adding sodium hydrogen carbonate little bylittle. The aqueous layer was separated, washed with a solvent mixtureof 30 ml of tetrahydrofuran and 60 ml of ethylacetate, and then adjustedto pH 2.4 to 2.8 using 2N-HCl. The crystal thus precipitated was stirredfor 1 hour under ice-bath, filtered, washed with 30 ml of water anddried to obtain 5.5 g (Yield 92%) of the title compound as a pale yellowsolid.

HPLC Purity: 99.2%;

IR(KBr, cm⁻¹): 3300, 1780, 1665, 1180, 1130;

¹ H-NMR(DMSO-d_(G)) δ: 3.5, 3.80(2H,ABq,J=18 Hz), 5.2(1H,d,J=5 Hz), 5.3;(1H,d,J=10 Hz), 5.6(1H,d,J=17 Hz), 5.8(1H,dd,J=8 Hz,5 Hz), 6.7(1H,s),6.9(1H,dd,J=17 Hz,10 Hz), 7.1(2H,brs), 9.4(1H,d,J=8 Hz), 11.3 (1H,brs).

EXAMPLE 7

10.0 g (10.2 mmol) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluenesulfonic acid•2 N,N-dimethylacetamide was dissolved in 20ml of methanol and then 20 ml (0.26 mol) of trifluoroacetic acid and 10ml (92 mmol) of anisole were added thereto. After the mixture wasstirred for 5 hours at 40 to 45° C., the methanol contained therein wasremoved under reduced pressure. The residue was dispersed in 200 ml ofethylacetate, and then the resulting solution was stirred for 30 minutesand filtered. The pale yellow solid thus obtained was dried anddissolved in 60 ml of water, 30 ml of tetrahydrofuran and 60 ml ofethylacetate. The pH of the solution was adjusted to 5.5 to 6.5 byadding sodium hydrogen carbonate little by little. The aqueous layer wasseparated, washed with a solvent mixture of 30 ml of tetrahydrofuran and60 ml of ethylacetate, and then adjusted to pH 2.4 to 2.8 using 2N-HCl.The crystal thus precipitated was stirred for 1 hour under ice-bath,filtered, washed with 30 ml of water and dried to obtain 3.6 g (Yield90%) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid as a pale yellow solid. The purity of the product determined byHPLC analysis was 99.4%, and IR and ¹ H-NMR data were identical to thosedescribed in Example 6.

EXAMPLE 8

To 5.0 g (5.1 mmol) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid•p-toluenesulfonic acid•2 N,N-dimethylacetamide was added 15 ml of85% formic acid and the mixture was stirred for 2 hours at roomtemperature. After tritylcarbinol thus precipitated was removed byfiltration, the filtrate was concentrated under reduced pressure. To theresidue were added 30 ml of water, 10 ml of tetrahydrofuran and 20 ml ofethylacetate. The pH of the solution was adjusted to 6.5 by addingsodium hydrogen carbonate little by little. The aqueous layer wasseparated, washed with a solvent mixture of 10 ml of tetrahydrofuran and20 ml of ethylacetate, and then adjusted to pH 2.4 to 2.8 using 2N-HCl.The crystal thus precipitated was stirred for 1 hour under ice-bath,filtered, washed with 10 ml of water and dried to obtain 1.9 g (Yield93%) of7β-[2-(2-aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid as a pale yellow solid. The purity of the product determined byHPLC analysis was 99.1%, and IR and ¹ H-NMR data were identical to thosedescribed in Example 6.

What is claimed is:
 1. A process for preparing cefdinir having thefollowing formula (I), ##STR9## characterized in that a tritylprotecting group in a cefdinir intermediate having the following formula(II), ##STR10## in which Ph represents phenyl, p-TsOH representsp-toluenesulfonic acid, and DMAC represents, N,N-dimethylacetamide, isremoved by reacting with an inorganic acid, an organic acid, or anacidic hydrogen ion exchange resin.
 2. A process for preparing acompound having the following formula (II), ##STR11## in which Phrepresents phenyl, p-TsOH represents p-toluenesulfonic acid, and DMACrepresents N,N-dimethylacetamide, characterized in that a reactive esterhaving the following formula (III), ##STR12## in which Z represents##STR13## or ##STR14## wherein R' represents C₁ -C₄ alkyl or phenyl,which is reacted with a 3-cephem derivative having the following formula(IV), ##STR15## in a solvent comprising DMAC in the presence or absenceof a base, and then p-toluenesulfonic acid is added thereto.
 3. Theprocess according to claim 1, wherein the inorganic acid is selectedfrom a group consisting of hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid and Lewis acid.
 4. The process accordingto claim 3, wherein the Lewis acid is selected from a group consistingof boron trifluoride, boron trifluoride ethyletherate, aluminumchloride, antimony pentachloride, ferrous chloride, stannous chloride,titanium tetrachloride and zinc chloride.
 5. The process according toclaim 1, wherein the organic acid is selected from a group consisting ofacetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid.
 6. The processaccording to claim 1, wherein the reaction is carried out in thepresence of a cation scavenger when a Lewis acid or an organic acid isused.
 7. The process according to claim 6, wherein the cation capturingagent is anisole.
 8. The process according to claim 1, wherein the acidis used in an amount of 1 to 20 equivalents with respect to the compoundof formula (II).
 9. A crystalline cefdinir intermediate having thefollowing formula (II): ##STR16## in which Ph represents phenyl,p-TsOHrepresents p-toluenesulfonic acid, and DMAC representsN,N-dimethylacetamide.
 10. The process according to claim 2, whereindiethylether, diisopropylether or ethylacetate is added in an amount of2 to 6 times by volume with respect to the reaction solvent as anadditional work-up procedure.
 11. The process according to claim 2,wherein p-toluenesulfonic acid is used in an amount of 1 to 3equivalents with respect to the 3-cephem derivative of formula (IV). 12.The process according to claim 2, wherein the reactive ester of formula(III) is used in an amount of 0.8 to 2.0 equivalents with respect to the3-cephem derivative of formula (IV).
 13. The process according to claim2, wherein the solvent is N,N-dimethylacetamide alone, or a mixture ofN,N-dimethylacetamide with one or more selected from a group consistingof ethanol, methanol, isopropanol, diethylether, tetrahydrofuran,dioxane, methylene chloride, chloroform, acetonitrile, ethylacetate andacetone.
 14. The process according to claim 2, wherein the reaction iscarried out at a temperature of -15 to 40° C.
 15. The process accordingto claim 2, wherein a tertiary amine is used as the base.
 16. Theprocess according to claim 15, wherein the tertiary amine istriethylamine or tri-n-butylamine.
 17. The process according to claim 2,wherein N-trimethylsilylacetamide or N,O-bistrimethylsilylacetamide isused in the absence of a base.